title: LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both.
abstract: OBJECTIVE
  New molecular targeted agents are needed for patients with non-small-cell lung cancer (NSCLC) who progress while receiving erlotinib, gefitinib, or both. Afatinib, an oral irreversible ErbB family blocker, has preclinical activity in epidermal growth factor receptor (EGFR [ErbB1]) mutant models with EGFR-activating mutations, including T790M.
  
  
  METHODS
  This was a Japanese single-arm phase II trial conducted in patients with stage IIIB to IV pulmonary adenocarcinoma who progressed after ≥ 12 weeks of prior erlotinib and/or gefitinib. Patients received afatinib 50 mg per day. The primary end point was objective response rate (complete response or partial response) by independent review. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.
  
  
  RESULTS
  Of 62 treated patients, 45 (72.6%) were EGFR mutation positive in their primary tumor according to local and/or central laboratory analyses. Fifty-one patients (82.3%) fulfilled the criteria of acquired resistance to erlotinib and/or gefitinib. Of 61 evaluable patients, five (8.2%; 95% CI, 2.7% to 18.1%) had a confirmed objective response rate (partial response). Median PFS was 4.4 months (95% CI, 2.8 to 4.6 months), and median OS was 19.0 months (95% CI, 14.9 months to not achieved). Two patients had acquired T790M mutations: L858R + T790M, and deletion in exon 19 + T790M; they had stable disease for 9 months and 1 month, respectively. The most common afatinib-related adverse events (AEs) were diarrhea (100%) and rash/acne (91.9%). Treatment-related AEs leading to afatinib discontinuation were experienced by 18 patients (29%), of whom four also had progressive disease.
  
  
  CONCLUSIONS
  Afatinib demonstrated modest but noteworthy efficacy in patients with NSCLC who had received third- or fourth-line treatment and who progressed while receiving erlotinib and/or gefitinib, including those with acquired resistance to erlotinib, gefitinib, or both.
authors.affiliation: Nobuyuki Katakami, Kobe City Medical Center General Hospital, Kobe; Shinji Atagi, National Hospital Organization Kinki-Chuo Chest Medical Center; Koji Takeda, Osaka City General Hospital; Kazuto Nishio, Kinki University, Osaka; Koichi Goto, National Cancer Center Hospital East, Chiba; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Takeshi Horai, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo; Akira Inoue, Tohoku University Hospital, Sendai; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Kunihiko Koboyashi, Saitama International Medical Center, Saitama; Katsuyuki Kiura, Okayama University, Okayama; Yoko Seki and Ryuichi Ebisawa, Nippon Boehringer Ingelheim; Nobuyuki Yamamoto, Shizuoka Cancer Center, Shizuoka, Japan; and Mehdi Shahidi, Boehringer Ingelheim, Bracknell, United Kingdom.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Katakami
authors.forename: Shinji
authors.initials: S
authors.lastname: Atagi
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Hida
authors.forename: Takeshi
authors.initials: T
authors.lastname: Horai
authors.forename: Akira
authors.initials: A
authors.lastname: Inoue
authors.forename: Yukito
authors.initials: Y
authors.lastname: Ichinose
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Koboyashi
authors.forename: Koji
authors.initials: K
authors.lastname: Takeda
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Yoko
authors.initials: Y
authors.lastname: Seki
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Ebisawa
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shahidi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib